ArticleAntimicrobial agents and chemotherapy2011
Recombinant phenotyping of cytomegalovirus UL54 mutations that emerged during cell passages in the presence of either ganciclovir or foscarnet.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- Drug Resistance Assessed in a Phase 3 Clinical Trial of Maribavir Therapy for Refractory or Resistant Cytomegalovirus Infection in Transplant Recipients.The Journal of infectious diseases · 2024Trial
- A new locus of foscarnet resistance in the cytomegalovirus UL54 DNA polymerase gene among uncharacterized mutations in recent clinical trials.Antiviral research · 2026Article
- Lactobacilli-Derived Postmetabolites Are Broad-Spectrum Inhibitors of Herpes Viruses In Vitro.International journal of molecular sciences · 2024Article
- Photodynamic Inactivation of Human Herpes Virus In Vitro with Ga(III) and Zn(II) Phthalocyanines.Viruses · 2024Article
- Detection of antiviral drug resistance in patients with congenital cytomegalovirus infection using long-read sequencing: a retrospective observational study.BMC infectious diseases · 2022Observational
- Analysis of Novel Drug-Resistant Human Cytomegalovirus DNA Polymerase Mutations Reveals the Role of a DNA-Binding Loop in Phosphonoformic Acid Resistance.Frontiers in microbiology · 2022Article
- Prevalence of UL97 gene mutations and polymorphisms in cytomegalovirus infection in the colon associated with or without ulcerative colitis.Scientific reports · 2021Article
- Hypersusceptibility of Human Cytomegalovirus to Foscarnet Induced by Mutations in Helices K and P of the Viral DNA Polymerase.Antimicrobial agents and chemotherapy · 2020Article
- Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2019Article
- Refractory cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation: when should genotypic drug resistance testing be requested?Bone marrow transplantation · 2018Article
- Foscarnet resistance mutations mapping to atypical domains of the cytomegalovirus DNA polymerase gene.Antiviral research · 2017Article
- How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients.Blood · 2016Article
- Novel Cytomegalovirus UL54 DNA Polymerase Gene Mutations Selected In Vitro That Confer Brincidofovir Resistance.Antimicrobial agents and chemotherapy · 2016Article
- New strategies against drug resistance to herpes simplex virus.International journal of oral science · 2016Review
- Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus.Frontiers in microbiology · 2016Article
- Mechanism of ganciclovir-induced chain termination revealed by resistant viral polymerase mutants with reduced exonuclease activity.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Detection of cytomegalovirus drug resistance mutations by next-generation sequencing.Journal of clinical microbiology · 2013Article
- Rapid detection of human cytomegalovirus UL97 and UL54 mutations directly from patient samples.Journal of clinical microbiology · 2013Article
- The biology of cytomegalovirus drug resistance.Current opinion in infectious diseases · 2011Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Selection of human cytomegalovirus variants in the presence of ganciclovir or foscarnet led to 18 DNA polymerase mutations, 14 of which had not been previously studied. Using bacterial artificial chromosome technology, each of these mutations was individually transferred into the genome of a reference strain. Following reconstitution of infectious viral stocks, each mutant was assessed for its drug susceptibility and growth kinetics in cell culture. Computer-assisted three-dimensional (3D) modeling of the polymerase was also used to position each of the mutations in one of four proposed structural domains and to predict their influence on structural stability of the protein. Among the 10 DNA polymerase mutations selected with ganciclovir, 7 (P488R, C539R, L545S, V787L, V812L, P829S, and L862F) were associated with ganciclovir resistance, whereas 2 (F595I and V946L) conferred only foscarnet resistance. Among the eight mutations selected with foscarnet, only two (T552N and S585A) conferred foscarnet resistance, whereas four (N408D, K500N, L802V, and L957F) had an impact on ganciclovir susceptibility. Surprisingly, the combination of mutations, some of which were not associated with resistance for a specific antiviral, resulted in increasing resistance effects. 3D modeling suggested that none of the mutated residues were directly involved in the polymerase catalytic site but rather had an influence on drug susceptibility by modifying the structural flexibility of the protein. Our study significantly adds to the number of DNA polymerase mutations conferring in vitro drug resistance and emphasizes the point that evaluation of individual mutations may not accurately reflect the phenotype conferred by multiple mutations.
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